Abstract
PurposeThe differentiated superficial cells of the urothelium restrict urine flow into the bladder wall. We have demonstrated that urothelial cells isolated from bladders of patients with interstitial cystitis/painful bladder syndrome (IC/PBS) fail to release PGE2 in response to tryptase. This study examines the expression of PGE2 synthesis and degradation enzymes in urothelial cells during differentiation.Materials and MethodsWe measured immunoprotein expression of cyclooxygenase-2 (COX-2), prostaglandin E2 synthase (PGES) and 15-hydroxyprostaglandin dehydrogenase (PGDH) in human urothelial cells and in immortalized urothelial cells isolated from the bladders of IC/PBS patients or normal subjects during stratification and differentiation produced by increased calcium and fetal bovine serum (Ca/FBS) in the culture medium for 1, 3 and 7 days.ResultsPGES immunoprotein expression increased during differentiation in normal and IC/PBS urothelial cells. COX-2 expression also increased in cells from normal patients following differentiation. Remarkably, no COX-2 expression was detectable in urothelial cells isolated from 3 out of 4 IC/PBS patients. PGDH immunoprotein expression decreased in normal cells after 1 and 3 days of Ca/FBS addition, but returned to normal after 7 days. PGDH expression was unchanged during differentiation at 1 and 3 days, but was more than 2-fold higher at 7 days compared to day 0 in the IC/PBS cells. Urothelial cells isolated from IC/PBS patients demonstrated no PGE2 release in response to tryptase under any of the experimental conditions studied.ConclusionsTaken together, our results indicate that PGE2 release is compromised during stratification and differentiation in IC/PBS urothelium and may contribute to impaired barrier function.
Highlights
Interstitial cystitis/painful bladder syndrome (IC/PBS) is associated with increased activated mast cell numbers in the bladder [1,2,3], impairment of the barrier function [4,5,6] of the urothelium and neurogenic inflammation [7,8,9]
Our results indicate that prostaglandin E2 (PGE2) release is compromised during stratification and differentiation in IC/PBS urothelium and may contribute to impaired barrier function
Bladder biopsies from patients diagnosed with IC/PBS have demonstrated an increase in the number of IL-6 positive mast cells, and mast cell mediators such as tryptase and histamine are detected in the urine of IC/PBS patients
Summary
Interstitial cystitis/painful bladder syndrome (IC/PBS) is associated with increased activated mast cell numbers in the bladder [1,2,3], impairment of the barrier function [4,5,6] of the urothelium and neurogenic inflammation [7,8,9]. Mast cells are the primary effectors of type 1 IgE-mediated immune reaction and release a battery of stored and newly formed mediators upon activation, including biogenic amines such as histamine, neutral proteases such as tryptase, chymase, cathepsin and carboxypeptidase, arachidonic acid metabolites, chemokines and cytokines. We have demonstrated previously that tryptase stimulation of human urothelial cells results in activation of calcium-independent phospholipase A2 (iPLA2) and increased release of prostaglandin E2 (PGE2) [10]. Since IC/PBS is associated with impairment of urothelial integrity, it is compelling to suggest that PGE2 may be beneficial in this disease
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